Natural Helper (NH) cells are newly discovered innate immune cells that produce T-helper type 2 (Th2) cytokines and promote protective type 2 immunity during helminth infection, or after influenza infection. The ontogeny of NH cells and their function in allergic diseases are not known. Strikingly, we find that NH cells have similar gene expression profile as T cell lineage progenitors, and that the development of NH cells is dependent on TCF-1, an essential transcription factor in early T cell development. We propose to determine the molecular pathways that underlie the development of NH cells. We will also examine the role of NH cells in the pathogenesis of allergic asthma. Studies in this proposal will improve our understanding of the generation and function of NH cells, which will inform therapeutic strategies to target NH cells for Th2 associated diseases. PUBLIC HEALTH RELEVANCE: T helper 2 (Th2) cytokines are central players in the pathogenesis of allergic asthma. Natural helper cells are newly discovered immune cells that were shown to be a major source of Th2 cytokines but neither their developmental origin nor their significance in asthma is understood. We propose to identify the cellular precursors and the signals that give rise to Natural helper cells. Using a mouse model we will also determine the role of Natural helper cells in the pathology of allergen-induced airway inflammation. Our study will provide important clues to targeting Natural helper cells as a novel therapeutic approach to Th2-driven (allergic) airway inflammation in asthma.